tbuckley/cabot-search huggingface dataset:
Safety and clinical activity of oleclumab (O) ± durvalumab (D) + chemotherapy (CT) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC): A phase 1b/2 randomized study.
Authors: Andrew L. Coveler, Matthew Reilley, Mark Zalupski, Teresa Macarulla, Christos Fountzilas, Eduardo Castanon Alvarez, Adnan Nagrial, Nataliya Volodymyrivna Uboha, Sophia Frentzas, Michael J. Overman, Anne M. Noonan, Wells A. Messersmith, Nick Pavlakis, Niharika B. Mettu, Paul Smith, Elina Murtomaki, Veronique Bragulat, Zachary A. Cooper, Rakesh Kumar, David Spigel
Journal: Journal of Clinical Oncology (2023)

4136 Background: In a phase 1 study, the anti-CD73 monoclonal antibody (mAb) O plus the anti-PD-L1 mAb D showed antitumor activity and manageable safety in previously treated pts with advanced PDAC (Overman et al, J Clin Oncol 2018;36[suppl 15]:abs 4123). Here we report a multicenter, open-label study of O ± D + CT in pts with mPDAC. Methods: Pts were ≥18 years old with ECOG PS 0–1. Part 1 was a dose escalation phase: in Cohort A, previously untreated (1L) pts received O 1500 or 3000 mg IV Q2W for 4 doses then Q4W + D 1500 mg IV Q4W, with Q4W gemcitabine and nab-paclitaxel (GnP). In Cohort B, pts with previous G-based CT (2L) received O 1500 or 3000 mg Q2W for 4 doses then Q4W + D 1500 mg Q4W, with Q4W mFOLFOX. The primary objective for Part 1 was safety and tolerability; secondary objectives included antitumor activity and pharmacokinetics (PK). Part 2 was an expansion phase in which pts were stratified by high/low tumoral CD73 expression by IHC. In Cohort A, 1L pts were randomized 1:1:1 to GnP alone (Arm A1), O + GnP (Arm A2) or O + D + GnP (Arm A3). O was given at the recommended phase 2 dose, 3000 mg. Cohort B did not proceed to dose expansion due to emerging therapies in 2L PDAC pts. The primary endpoint for Part 2 was investigator-assessed objective response rate (ORR) by RECIST v1.1; secondary included PFS, OS, safety, PK and antidrug antibody data. Results: As of November 11, 2022, 25 pts were treated in Part 1 (Cohort A, n=14; Cohort B, n=11), and 170 pts were treated in Part 2 (Arm A1, n=62; Arm A2, n=38; Arm A3, n=70). In Part 1, dose-limiting toxicities occurred in 1 pt (Cohort B, O 3000 mg: Gr 3 nausea and Gr 3 localized edema). Safety was generally similar in Parts 1 and 2. In Part 2, Gr ≥3 treatment-emergent adverse events (TEAEs) occurred in 85.5%, 89.5% and 90.0% of pts in Arms A1, A2 and A3 respectively, most commonly neutropenia (22.6%, 34.2% and 17.1%). In Part 2, TEAEs led to discontinuation in 11.3%, 23.7% and 24.3% of pts respectively. In Part 2, ORR was similar across Arms with a trend toward longer PFS and OS in Arm 3 vs Arm 1. There was a trend toward greater clinical benefit in pts with high CD73 expression when comparing Arm A3 vs Arm A1. Conclusions: O + D + GnP had similar safety and a trend toward improved outcomes compared to GnP. Clinical trial information: NCT03611556 . [Table: see text]
Use of immune checkpoint gene (ICG) signatures to identify selective enrichment of FGL1 and CEACAM1 in histologic subtypes of lung cancer.
Authors: Susrutha Puthanmadhom Narayanan, Yufei Huang, Taofeek K. Owonikoko
Journal: Journal of Clinical Oncology (2023)

e20527 Background: Immune checkpoint blockade has changed the management paradigm for lung cancer. Identification of vulnerable subsets using reliable predictive biomarkers is an area of unmet need. We systematically compared the pattern of expression of validated mediators of adaptive and innate immune response in clinical and histologic subsets of lung cancer using publicly available datasets. Methods: Gene expression data for lung adenocarcinoma (LUAD, N = 501) and and lung squamous cell carcinoma (LUSC, N = 491) was obtained from The Cancer Genome Atlas. We compared the expression of ICGs between LUSC and LUAD using DESeq2 and estimated the proportion of different immune cells in the tumor microenvironment by CIBERSORT. An expanded panel of ICG signatures from MSigDB was compared between LUSC and LUAD using gene set variation analysis (GSVA). Weighted gene co-expression network analysis (WGCNA) identified modules of immune checkpoint inhibitor genes with significant correlation with histology, which were further investigated for biologic pathway involvement and survival analysis using Ingenuity Pathway Analysis and Gene Expression Profiling Interactive Analysis (GEPIA2), respectively. Results: Majority of the ICGs had a higher expression in LUAD than LUSC with the strongest differential expression recorded for FGL1 (LogFC = 6.2, FDR = 1.2E-239) and CEACAM1 (LogFC = 1.4, FDR = 2E-71). Treg cells and monocytes were higher in LUAD while NK cells and macrophages were higher in LUSC. There was no difference in CD8(+) T cell population by histology. Genesets related to PD1 signaling from MSigDB had significantly higher GSVA scores in LUAD than LUSC. WGCNA identified 2 modules containing immune checkpoint genes – one module containing 15 of the 23 ICGs involved in allograft rejection, interferon gamma response, interferon alpha response, IL6-signaling, IL2-signaling and TNF-alpha signaling showed moderate correlation with LUAD (module-trait correlation = 0.3, P = 8e-26). A second module with 4 ICGs ( FGL1, LGALS3, CEACAM1, PVRL2) enriched in pathways related to carbohydrate and lipid metabolism (galactose degradation, gamma-linolenate biosynthesis) showed very strong correlation with LUAD (module-trait correlation = 0.85, P = 5e-278). Additional comparison by gender and smoking status along with external validation using independent dataset is ongoing. Conclusions: ICG expression profile differs between LUAD and LUSC with a stronger expression profile in LUAD than LUSC.
The prognostic effect of <i>ADH1B</i> and <i>ALDH2</i>in lung adenocarcinoma.
Authors: Ying Zhang, Jinan Ma, Hongchun Du, Ying Shi, Saffron A.G. Willis-Owen, Miriam F. Moffatt, Youming Zhang
Journal: Journal of Clinical Oncology (2023)

e15167 Background: Alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) are major enzymes involved in the metabolism of carcinogenic acetaldehyde, converting alcohol to acetaldehyde and detoxifying acetaldehyde to harmless acetic acid, respectively. To investigate the role of ADH isoenzymes and ALDH isoenzymes in the development of lung adenocarcinoma (LUAD), we performed a retrospective analysis of gene expression. Methods: RNA sequencing data derived from 497 tumour samples and 54 adjacent normal samples were obtained from the Cancer Genome Atlas (TCGA) database. The transcript levels of ADH and ALDH family genes were compared between tumour tissue and adjacent normal tissue through a Wilcoxon test. The results were validated in transcriptomic data from 111 lung cancer patients available as part of a prior study. The diagnostic and prognostic value of ADH and ALDH family genes was further investigated by survival analysis and nomogram through the TCGA database. Insights into the mechanism of action were gained through gene set enrichment analysis (GSEA). Results: Numerous ADH and ALDH family genes showed nominally significant differential expression between tumour and adjacent normal tissues. The expression levels of ADH1B and ALDH2 showed significant and replicable depression in tumour tissue. Low expression of ADH1B and ALDH2 was associated with worse overall survival, with the combination of these genes providing greater prognostic value than the additive effects of these genes individually in the TCGA database. ADH1B and ALDH2 transcript levels were linked with the regulation of metabolism, cell cycle, DNA repair and cancer-associated pathways. A risk score model for predicting LUAD prognosis was developed and showed good performance in predicting 1, 3 and 5-year overall survival (OS). Consistent with TCGA results, our 111-patient replication dataset showed that the tumour-specific depression was most pronounced for ADH1B, and the lower expression was associated with vascular, pleural and lymphatic invasions. Moreover, smoking status and/or cumulative smoking history do not provide a direct, clinically accessible proxy for tumour ADH1B or ALDH2 expression. Conclusions: The combination of ADH1B and ALDH2 are potential prognostic markers in LUAD and may have utility as an independent clinical factor for evaluating the prognosis of LUAD.
Updated results from a phase 2 study of the oral vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor rivoceranib for recurrent or metastatic (R/M) adenoid cystic carcinoma (ACC).
Authors: Hyunseok Kang, Myung-Ju Ahn, Bhumsuk Keam, Daniel W. Bowles, Deborah J.L. Wong, Alan Loh Ho, Sung-Bae Kim, Francis P. Worden, Tak Yun, Seong Jang, Xianzhang Meng, Glenn J. Hanna
Journal: Journal of Clinical Oncology (2023)

6040 Background: ACC is a rare tumor that overexpresses VEGF, primarily affecting salivary glands. Often indolent, it can progress, with metastases common in the lungs, liver, and bone. There are no FDA-approved systemic treatments (tx) for R/M ACC. Rivoceranib is an oral tyrosine kinase inhibitor (TKI) that potently and selectively inhibits VEGFR2. Methods: In this single-arm, open-label multicenter trial, patients (pts) with R/M ACC with evidence of ≥20% progression by RECIST v1.1 or new lesions within the preceding 6 months (mos) were eligible, with no limit on prior tx. Pts received rivoceranib 700 mg daily until disease progression or withdrawal with pre-planned dose reductions for toxicity. Primary endpoint was overall response rate (ORR) per RECIST v1.1 by investigator (INV) and by Independent Review Committee (IRC). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), time to progression (TTP), overall survival (OS), and safety exploratory analysis included disease control rate (DCR) and ORR using CHOI criteria by IRC. Results: As of 11/2022, 80 pts (72 evaluable) were enrolled in the US and Korea (53% male; median age, 54 yrs), and 6 pts remain on tx. Primary tumor sites: major (34%) and minor (59%) salivary glands and other (8%). 74 pts (93%) had metastatic disease. 61.3% had prior systemic tx (18% prior VEGFR TKI). INV and IRC-assessed efficacy data are listed in the table. ORR by CHOI was 52.5% (53.1% VEGFR TKI-naive and 50% VEGFR TKI treated). mOS was 25.3 mos (28.3 mos VEGFR TKI-naïve and 22.6 mos VEGFR treated). Common adverse events (AEs) were hypertension (66%), fatigue (64%), and nausea (54%). Grade ≥3 AEs that occurred in &gt;5% of pts were hypertension (43%), stomatitis (8%), fatigue and anemia (6% each). There were 4 Grade 5 AEs (2 epistaxis [1 related], 1 acute respiratory failure, 1 respiratory failure). Conclusions: Updated results with additional 9-month follow-up data continue to demonstrate that Rivoceranib has clinical efficacy and a manageable safety profile in pts with R/M ACC. Clinical trial information: NCT04119453 . [Table: see text]
Circulating tumor DNA methylation marker-based minimal residual diseases detection and recurrence monitoring of cancer.
Authors: Huiyong Wang, Xiaobao Pan, Lin Wang, Chao Li, Chao Ma, Shuai Yu, Fanyang Meng, Jing Liu, Liang Liu, Zhanbo Cao
Journal: Journal of Clinical Oncology (2023)

e15172 Background: Circulating tumor DNA (ctDNA) has been heralded as a promising tool to detect residual disease, relapse, and monitor treatment response by detecting molecular residual disease (MRD) in solid tumors. Numerous previous studies have demonstrated the molecular characteristics of ctDNA, such as the mutational landscape, single-nucleotide variations, copy number variations, and methylation landscape. Based on the methylation characteristics of ctDNA, we developed a novel MRD evaluation system (PcMM-qMSP) with ctDNA methylation markers, and evaluated the association of changes in ctDNA level with clinical outcome. Methods: We used sequencing data from public databases for data mining by clinical Natural Language Processing (NLP) to screen the pan-cancer ctDNA methylation markers (PcMM). A PcMM-based MRD detection method was established by quantitative methylation-specific PCR (qMSP). Moreover, 99 clinical blood samples [lung cancer (41), colorectal cancer (18), gastric cancer (5), pancreatic adenocarcinoma (16), liver cancer (6), cervical cancer (3), ovarian cancer (4), breast cancer (3), and unknown (3)] were collected to evaluate the consistency of ctDNA level between PcMM-qMSP and next-generation sequencing (NGS). Results: We evaluated the precision, including within-batch (intra) and between-batch (inter) reproducibility. PcMM-qMSP showed coefficients of variation (CVs) of the intra- and inter-batch assay of 0.42-0.65% and 0.05-0.27%, the accuracies were 100%. Best-in-class assays demonstrated a limit of detection (LoD) of approximately 30 copies of methylated DNA, with lower LoD at 10 copies. The evaluation results of 99 pan-solid tumor blood samples showed that the consistency of PcMM-qMSP and NGS in ctDNA level assessment was 0.82. The specific data are shown in the Table. Conclusions: PcMM is a pan-tumor specific methylation biomarker. The results demonstrated that PcMM-qMSP and NGS were highly functionally consistent for estimating ctDNA level. PcMM-qMSP detection time is less than 24 hours and costs USD 300 as compared to NGS, which takes seven days and costs USD 900. Hence, PcMM-qMSP is economical, rapid, accurate and highly sensitive for detecting pan-solid tumors. [Table: see text]
Phase 2 study of olaparib (without ADT) in men with biochemically recurrent prostate cancer (BCR) after prostatectomy.
Authors: Catherine Handy Marshall, Benjamin A. Teply, Su Jin Lim, Hao Wang, Shifeng S. Mao, William Kevin Kelly, Channing Judith Paller, Mark Christopher Markowski, Samuel R. Denmeade, Michael Anthony Carducci, Mario A. Eisenberger, Serina King, Rana Sullivan, Tamara L. Lotan, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2023)

5087 Background: The natural history of BCR after prostatectomy is variable and current treatment approaches include observation, salvage radiation, or androgen deprivation therapy (ADT), although many men wish to defer such therapy. We hypothesized that olaparib, now approved for use in certain men with metastatic castration resistant prostate cancer, might be an alternative option for men with high-risk BCR. Methods: This was a single arm, phase 2 trial (NCT03047135) conducted at 4 US sites. Subjects with biochemically recurrent (M0) prostate cancer, post prostatectomy, with a PSA doubling time of ≤6 months and an absolute PSA of ≥1.0 ng/mL were eligible. Patients were NOT selected based on the presence of homologous recombination repair (HRR) mutations. 51 patients were treated with olaparib 300mg twice per day, until radiographic or symptomatic progression, PSA doubling from baseline value, or drug-related toxicity. The primary endpoint was PSA50 response (50% PSA decline from baseline). Secondary endpoint was PSA progression free survival (PFS). Patients were required to undergo tissue-based next generation sequencing on the radical prostatectomy specimen to determine the presence of mutations in HRR genes ( ATM, BARD1, BRCA1/2, BRIP1, CDK12, CHEK1/2, FANCA/E/L, PALB2, RAD51B/C/D). A prespecified endpoint was to assess PSA responses in HRR[+] and HRR[–] cohorts separately. Results: Mean age was 64 years (SD 7), and 92% (47/51) of patients were White. Mean baseline PSA doubling time was 2.9 (SD 1.5) months. 55% (28/51) of pts had Gleason 6-7, 14% (7/51) had Gleason 8, and 31% (16/51) had Gleason 9-10. 86% (44/51) of patients had previously received salvage radiation. 27 patients harbored HRR mutations, the most common of which were BRCA2 (n=11), CHEK2 (n=6), and ATM (n=6). The overall PSA50 response rate was 24% (12 of 51)(95% CI 0.13, 0.38), with no responses in the HRR[–] group and 44% (12/27) PSA50 responses in the HRR[+] group (95%CI 0.26, 0.65). All 11 of the participants with a BRCA2 mutation achieved a PSA50 response. The median PSA PFS was 22 months in the HRR[+] group and 13 months in the HRR[–] group (HR 0.71; 95% CI 0.31, 1.63). Most AEs were low grade. The most common all-grade AEs were fatigue, nausea, leukopenia, anemia, and dysgeusia. Grade-3 AEs were leukopenia (9.8%), ALT/AST increase (3.9%), and anemia (2.0%). There were no grade 4–5 AEs. Conclusions: Olaparib, in the absence of ADT, can be safely administered and demonstrated activity in men with BCR prostate cancer and HRR mutations, especially for BRCA2 mutations. Additional studies to further evaluate olaparib in these patients are indicated. Clinical trial information: NCT03047135 .
Arterial chemotherapy in advanced hepatocellular carcinoma: An evolutionary trajectory exploration and pooled outcome analysis.
Authors: Qi-Feng Chen, Ning Lyu, Ming Zhao
Journal: Journal of Clinical Oncology (2023)

e16125 Background: Hepatic artery infusion chemotherapy (HAIC) is widely used for the treatment of advanced hepatocellular carcinoma (HCC), particularly in East Asia. However, there have been inconsistent conclusions on the effectiveness of HAIC in previous studies, and the analysis landscape regarding relevant articles and clinical trials is lacking on this topic. We conducted a bibliometric analysis to explore the development of HAIC, and a pooled analysis using individual patient data to evaluate the outcomes of HAIC in advanced HCC. Methods: The Web of Science Core Collection was searched from its earliest records until October 2022, to identify studies associated with HAIC for advanced HCC. Relevant documents were collected and analyzed using R bibliometrix. During the same period, two international clinical trial registered platforms, ClinicalTrials.gov and ChiCTR.org, were searched for oxaliplatin-based HAIC utilization in HCC. A total of 845 patients treated with HAIC or its combination therapy from 17 pre-registered studies were analyzed to assess the overall survival (OS), progression-free survival (PFS), objective response rate (ORR per Response Evaluation Criteria in Solid Tumors (RECIST)), disease control rate (DCR per RECIST), and adverse events (AEs). Results: We identified 539 studies and derived the evolutionary trajectory of HAIC from the perspective of scientometry. Contributions of publications were presented at the country, institution, and author levels. Conversion therapy, Folfox, oxaliplatin and immunotherapy became new research foci. A total of 88 registered trials were identified and a comprehensive landscape of these trials was provided. Further interactive exploration of the trials was accessible through a HAICshiny application (https://sysucc.shinyapps.io/clinical-trial-of-HAIC-FO/). The OS was 13.7 months (95% confidence interval (CI) 12.2-15.3), and the corresponding times were 13.2, 13.8, 12.8, and 13.7 months in the cisplatin, oxaliplatin, HAIC monotherapy, and concomitant therapy subgroups, respectively. The corresponding PFS was 7.0 months (95% CI 6.5-7.8) in the whole cohort and 5.2, 7.7, 7.6, and 6.8 months in the subgroup cohorts. According to RECIST criteria, ORR and DCR reached 0.34 and 0.80, respectively. Comparable survival and tumor response were observed between the HAIC and its combination therapy groups. The incidence of AEs was identified, and most of them were manageable. Conclusions: This study illustrates the evolutionary trajectory of HAIC from the perspective of scientometry. The efficacy outcomes of HAIC in the treatment of advanced HCC were verified with manageable safety profiles. Further trials regarding HAIC implementation are emerging, and more effort is required to improve the quality of trials.
Multi-dimensional cell-free DNA-based liquid biopsy and early detection of gastric cancer.
Authors: Yu Pengfei, Min Wu, Guangyu Ding, Hua Bao, Yian Du, Zhiyuan Xu, Litao Yang, Jingquan Fang, Xingmao Huang, Qian Lai, Jia Wei, Junrong Yan, Shanshan Yang, Peng He, Haimeng Tang, Xue Wu, Yang Shao, Dan Su, Xiangdong Cheng
Journal: Journal of Clinical Oncology (2023)

4060 Background: Gastric cancer is one of the most common cancer types. Most patients were diagnosed at advanced stages and experienced poor prognosis. A non-invasive assay for the detection of early-stage gastric cancer is highly desirable for reducing the gastric cancer-associated mortality. Methods: We prospectively collected a study cohort of 249 participants including 110 pathologically confirmed with stage I-II gastric cancer and 139 with non-cancerous conditions. A plasma sample was collected from each patient before conventional screening modalities for gastric cancer. We performed whole-genome sequencing with plasma samples and profiled four types of cell-free DNA (cfDNA) characteristics, fragment size pattern, copy number variation, nucleosome coverage pattern, and single nucleotide substitution. We used these differential profiles to develop an ensemble model to identify gastric cancer patients from non-cancer individuals. We further collected a validation cohort consisting of 73 gastric cancer patients and 94 non-cancer individuals to validate the cfDNA-based assay. Additionally, we compared the performance of our assay and conventional gastroscopy in a hypothetical 100,000 screening population by Monte Carlo simulation. Results: The liquid biopsy assay that incorporated four types of cfDNA characteristics was able to identify early-stage gastric cancer patients from non-cancer individuals at an AUROC of 0.962 in the study cohort and 0.972 in the validation cohort. At a specificity of 92.1% (128/139), it achieved a sensitivity of 88.2% (97/110) in the study cohort. With this threshold, in the validation cohort, 91.5% (86/94) of healthy individuals and 91.8% (67/73) of gastric cancer patients were correctly identified. In both study and validation cohorts, the inferred probabilities of cancer showed consistent trends to increase with pathological stages in the cancer group and disease statuses in the non-cancer group. Of note, our approach detected all gastric tumors located in the cardia and fundus (100.0%, 19/19), which could be challenging for gastroscopic examination. Additionally, through in-silico simulations, we showed that our cfDNA-based non-invasive assay may detect 96.3% more gastric cancer cases than conventional gastroscopy owing to higher sensitivity and anticipated better participant compliance in a large hypothetical screening population. Conclusions: We introduced a liquid biopsy assay using multiple dimensions of cfDNA characteristics that could accurately identify early-stage gastric cancer from non-cancerous conditions. As a cost-effective non-invasive approach, it may provide population-wide benefits for the early detection of gastric cancer.